rs142108245

chr15-33841994-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001036.6(RYR3):c.13168A>G(p.Asn4390Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000671 in 1,603,500 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N4390S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (16 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.78

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009970337).
• BP6: Variant 15-33841994-A-G is Benign according to our data. Variant chr15-33841994-A-G is described in ClinVar as [Benign]. Clinvar id is 531174.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000684 (992/1451156) while in subpopulation EAS AF= 0.0209 (824/39476). AF 95% confidence interval is 0.0197. There are 16 homozygotes in gnomad4_exome. There are 514 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.13168A>G	p.Asn4390Asp	missense_variant	91/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.13168A>G	p.Asn4390Asp	missense_variant	91/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00146 AC: 338 AN: 231778 Hom.: 6 AF XY: 0.00129 AC XY: 161 AN XY: 125176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000912

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0172

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.000348

GnomAD4 exome AF: 0.000684 AC: 992 AN: 1451156 Hom.: 16 Cov.: 31 AF XY: 0.000713 AC XY: 514 AN XY: 720630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000690

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0209

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000994

Gnomad4 OTH exome AF: 0.000783

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000958 Hom.: 5

Bravo AF: 0.000759

ExAC AF: 0.00146 AC: 176

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	17
Dann	Benign	0.83
DEOGEN2	Uncertain	0.43	T;.;.;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.
MutationTaster	Benign	0.83	N;N
PrimateAI	Benign	0.38	T
Polyphen		0.27	B;B;.;.;.;.
Vest4		0.31
MVP		0.89
MPC		0.27
ClinPred		0.058	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142108245; hg19: chr15-34134195; COSMIC: COSV66780639; COSMIC: COSV66780639;